Phenothiazine derivatives



United States Patent Office 3,519,622 Patented July 7, 1970 US. Cl. 260-243 14 Claims ABSTRACT OF THE DISCLOSURE This disclosure is concerned with phenothiazines useful as anti-inflammatory agents.

This application is a continuation-in-part of my copending application Ser. No. 413,974, filed Nov. 25, 1964, now abandoned.

The present invention relates to novel substituted phenothiazine carboxylic acids, to their sulfoxide and sulfone derivatives, and to methods for producing same.

The new compounds have utility as biologically active agents. More specifically, these compounds have antiinflammatory activity.

The novel substituted phenothiazines of this invention are represented by the following general structural fomrula:

FORMULA I wherein W is hydrogen or alkyl from one to five carbon atoms;

Y represents COR, CH OH, or (CH COR, with said Y being limited to the one or four position;

It represents an integer one or two;

R represents hydroxy, alkoxy, mercapto, dialkylaminoalkoxy, or NRR", NHNH or NHOH, the alkyl moieties each having one to three carbon atoms;

R' and R" represent hydrogen, alkyl, or dialkylaminoalkyl, the alkyl moieties each having one to three carbon atoms;

X and X represent at least one of H, OH, CN, CF halogen, NO NH CH S, CF O, CF S, CH SO, CF SO, CH SO CF SO RIIIRIII/NSOF AlkCO, lower alkyl straight or branched to five carbon atoms, lower alkoxy to five carbon atoms, phenyl,

CRHIRHIIOH advantageously CF R and R"" represent hydrogen or alkyl having one of three carbons;

Alk is alkyl having one to three carbon atoms;

X" represents one of H, OH, CN, CF halogen, CH S, CF O, CF S-, CH SO, CF SO,

CF SO R"R"NSO AlkCO, or lower alkyl to five carbon atoms; advantageously CF but X, X and X" are never all hydrogen; and

Z represents S, S0 or S0 advantageously S.

It is preferred to use as the novel anti-inflammatory compositions, a compound of the general structural Formula II below:

COR

FORMULA 11 wherein R represents hydroxy, alkoxy, mercapto, dialkylamin alkoxy or NR'R, NHNH or NHOH, the alkyl moieties each having one to three carbon atoms;

R and R" represent hydrogen, alkyl, or dialkylaminoalkyl, the alkyl moieties each having one to three carbon atoms;

X and X represent at least one of H, OH, CF halogen, NH CF 0, CH S, CF S-, CH SO-, CF SO-, CH SO CF SO R'R"NSO AlkCO, lower alkyl straight or branched to five carbon atoms, phenyl or CRR""OH, advantageously CF with one of X and X being limited to the 8-position;

X represents one of H, CF halogen, CH S, CF S CH SO, CF SO, CH SO CF SO R"R"NSO AlkCO, or lower alkyl to five carbon atoms, advantageously CF but X, X and X" are never all hydrogen;

R" and R" represent hydrogen or alkyl having one to three carbons; and

Alk is alkyl having one to three carbon atoms.

The 8-trifluoromethylphenothiazine-l-carboxylic acid compound of Formula I is especially advantageous.

METHOD A The substituted phenothiazines of the instant invention are prepared as shown by the following synthetic scheme:

BuLi

co X \N X Li i ILi in (IIIa) (IIIb) g N N l H X H X H020 Iva) (IVb) 002a Using a non-polar organic solvent, such as ether, a solution of an appropriately substituted phenothiazine is treated with butyl lithium under nitrogen to give an adduct of Formula IIIa or IIIb. After adequate time, up to several hours, has been allowed to complete the reaction in the range to 30, preferably, to C., the reaction mixture is quickly poured onto powdered Dry Ice, acidified with dilute mineral acid to neutralize the alkali, with an organic layer forming. The organic layer is extracted with dilute alkali and the extract acidified with dilute mineral acid to low pH to yield a solid.

After purification and decolorization of this material, while in an alkali solution, it is reacidified with dilute phosphoric acid to precipitate a solid product which contains both isomers, IVa and IVb.

This precipitated solid may be chromatographed to elute the separate isomers or it may be recrystallized from a mixture of glacial acetic acid-trifiuoro acetic acid to give the carboxylic acid derived from compound II.

METHOD B The claimed substituted phenothiazines are also prepared by another synthetic scheme starting with a substituted diphenyl sulfide and employing the Smiles rearrangement (I. C. S. 1935, p. 340):

COOR COOR X Ga 0o In the above scheme, M represents an alkali metal; R represents lower alkyl; and X, X and X are as previously defined.

An organic acid solution of a lower alkyl ester of a 2 [2' aminophenylmercapto]3-nitrobenzoate, having other appropriate substituents on the phenyl rings, is acylated by the slow addition of an acid anhydride, e.g. acetic anhydride. After allowing the reaction to go to completion at room temperature, the reaction mixture is concentrated to form a semicrystalline residue which is now redissolved in acetone and then treated with an alcoholic alkali metal hydroxide solution under refluxing conditions, yielding a lower alkyl ester of the appropriately substituted phenothiazine carboxylic acid.

The above ester (VIII), upon further redissolution in ether, filtration, concentration of the filtrate, and treatment with warm alcoholic alkali metal hydroxide gives an impure product. Water dissolution of the isolated produce, decolorizing with charcoal, and acidification of the cooled filtrate with an organic acid, such as acetic acid, yields the pure product as a crystalline solid, i.e. R represents hydrogen.

METHOD C A more convenient method for the synthesis of substituted phenothiazine carboxylic acids comprises heating together, preferably at reflux temperature, equimolar mixtures of an appropriately monoor di-substituted-2- aminothiophenol (in the form of the metal salt, an acid addition salt, or the free base) and an appropriately substituted 2 halo 3 nitrobenzoic acid in a suitable polar solvent, such as the amides, preferably N,N-dimethylformamide, with three or more equivalents of an alkali metal hydroxide or carbonate for several hours, as shown by the following synthetic scheme. Ha is halogen, preferably bromo.

C 0 OH X I 0 SH HaaV H Strong base Dimethylformamide NHz N02 Heat; X

X XII N J X H ([J O O H (VIIIa) The cooled mixture is poured into dilute acetic acid to precipitate the appropriately substituted phenothiazine carboxylic acid.

The sulfoxide and sulfone derivatives of the appropriately substituted phenothiazine carboxylic acids of Formula I are prepared as shown in the following synthetic The sulfoxide derivatives represented by Formula IX are prepared conveniently by oxidizing the substituted phenothiazine carboxylic acid in an unreactive solvent, such as chloroform, with one equivalent of an oxidizing agent, preferably m-chloroperbenzoic acid.

The corresponding sulfur dioxide derivatives represented by Formula X are prepared by oxidizing the sub stituted phenothiazine carboxylic acid in glacial acetic acid with at least two equivalents of an oxidizing agent, preferably an excess of 30% hydrogen peroxide at a temperature up to the reflux level of the reaction mixture.

Compounds of the structure of Formula VIII, IX, and X may readily be converted to the analog wherein the hydrogen of the carboxylic acid is a dialkylaminoalkyl moiety. Starting with a compound of the Formula I, wherein R is hydroxy, it is converted to an alkyl ester by heating in alcohol with a dialkylaminoalkyl halide to give another compound of Formula I, wherein R is diethylaminoethyloxy, for example.

Compounds with the structure of Formula I wherein Y is CSR, a sulfur derived acid, are prepared by reacting a substituted phenothiazine acid chloride with a solution, preferably alcoholic, of sodium or potassium hydrosulfide. The resultant salt of the thio-acid is converted to the free acid by acidification of its aqueous solution with mineral acid.

Compounds with the structure of Formula I wherein Y is -CH OH are prepared from the appropriate acid by lithium aluminum hydride reduction in a non-polar solvent, preferably ethyl ether.

Compounds with the structure of Formula I wherein Y is --(CH COR are prepared by alkaline hydrolysis 0f the appropriate nitrile or by carbonation of a suitable Grignard reagent according to the following scheme:

in 400 ml. of dry ether under nitrogen is cooled and maintained at 0-l0 C. while 382 ml. of a hexane solution X S X" X S X" XXV X" P01 KCN o o r l 1 -l l O N N X H X H 1 X fi CHiOH HzCl CHaON l fig. KOH

X I! I! S 3 92 o1 0! lo! N W g V CHzMgCl 47H: C 0211 Treatment of compounds with structure Formula I in which one or all of X, X or X" are equal to alkoxy with pyridine hydrochloride at elevated temperatures, preferably 135 to 150 0, results in the corresponding compounds in which the alkoxy has been converted to a hydroxy group.

The invention includes the pharmaceutically acceptable non-toxic salts of the above defined esters (Formula I where R represents dialkylaminoalkoxy), which are formed from non-toxic organic bases and inorganic acids.

The bases having the structural formula noted above may also be used in the form of their nontoxic salts formed by reacting the bases with either a pharmaceutically acceptable organic or inorganic acid, such as hydrochloric, hydrobromic, maleic, pamoic, ethanedisulfonic, sulfuric, phosphoric, sulfamic, etc., acids or active quaternary forming compounds, such as lower alkyl bromides, iodides or chlorides, ethylene chlorohydrin, methyl sulfate and benzyl halides. These equivalent salts are prepared by methods well-known to the art. Preferably the hydrochloride or sulfate salt is used. It will be recognized that up to three molar equivalents of acid per mole of base may be optionally used.

The invention also includes within its scope the pharmaceutically acceptable non-toxic salts of the above defined acids (Formula II where R represents hydroxy),

which are formed from non-toxic organic and inorganic bases. Such salts are easily prepared by methods known to the art. The acid is reacted with either the calculated amount of organic or inorganic base in aqueous miscible solvent, such as acetone or ethanol with isolation of the salt by concentration and cooling, or by treatment of the acid with an excess of the base in an aqueous immiscible solvent, such as ethyl ether or chloroform, the desired salt thereby separating directly. Any salt whose cation is non-toxic, pharmaceutically acceptable and stable may be formed, such as the ammonium, trimethylammonium or other nitrogen containing salts, but the alkali metal salts are preferred, especially the sodium and potassium salts. These salts are formed by reaction of the acids with the hydroxides such as ammonium hydroxide, sodium hydroxide or potassium hydroxide in a suitable aqueous medium.

The above compounds where R in Formula I equals NRR' are prepared conveniently by reacting the substituted phenothiazine acid chloride with ammonia (preferably anhydrous) or an appropriate amine in a suitable solvent (preferably organic in nature).

The following working examples are exemplary of the preparation of the novel compounds of this invention and are not to be construed as limitative thereof.

Example 1.Preparation of 2-trifluoromethylphenothiazinc-l-carboxylic acid of the structural Formula IVb A solution of 16 g. of 2-trifluoromethylphenothiazine of butyl lithium (10.5 g. per ml.) is added thereto. The stirred solution is maintained at 5-10 C. for six hours at which time the entire mixture is poured rapidly into crushed Dry Ice. Then this cooled solution is stirred with dilute hydrochloric acid (10% conc.) until free of alkali. The organic layer is then extracted with aqueous sodium hydroxide (1% conc.) until a sample of the extract gives practically no separation or acidification. The combined aqueous extracts are acidified to a pH of 2 with dilute hydrochloric acid and oily separation is stirred until solidification. The solid is removed and washed with water.

The crude solid is redissolved in 300500 ml. of aqueous sodium hydroxide. The colored solution is decolorized with Darco and filtered, the filtrate being cautiously adjusted to pH 6 with aqueous phosphoric acid (25% conc.). This is stirred at room temperature for approximately one hour at which time the precipitated solid is removed.

This latter solid is purified by redissolving in 75 ml. of hot glacial acetic acid. The hot solution is filtered and the filtrate is diluted with an equal volume of trifiuoro acetic acid. The filtrate is cooled and the crystalline separated solid is collected, washed with cold petroleum ether and dried to give a yellow-orange solid, Z-trifluoromethylphenothiazine-l-carboxylic acid, M.P. 199-200 C.

Example 2.Preparation of 8-t rifiuoromethylphenothiazine-l-carboxylic acid of the structural Formula Wu.

The crude mixture of phenothiazine acids (0.7 g.) of Example 1 is chromatographed on alumina (Woelm, Activity No. 4) using 1% triethylamine in methanol as the developing agent. Three fractions developed: a fast moving visible band (Z-trifiuoromethylphenothiazine), an intermediate visible band (Z-trifluoromethylphenothiazinel-carboxylic acid) and then a slow moving visible band. Eluates containing the last fraction are concentrated under reduced pressure. These are dissolved in dilute alkali, filtered, and the filtrate is adjusted to pH 5 with phosphoric acid (50% conc.). A yellow crystalline solid (8-trifluoromethylphenothiazine 1 carboxylic acid) is separated, washed with water, and dried, M.P. 242- 245 C.

Example 3.Preparation of ethyl 8 trifluoromethylphenothiazine-l-carboxylate of the structural Formula VIII A solution of methyl 2-[2'-amino-4'-trifiuoromethylphenylmercapto]-3-nitrobenzoate (10.6 g.) in 75 ml. of formic acid (98100% conc.) is stirred as 24 ml. of acetic anhydride is added drop-Wise. The temperature of the reaction rises to about 42 C. after which the reaction mixture is allowed to sit at room temperature overnight. The mixture is concentrated under reduced pressure to a semi-crystalline residue which is redissolved in ml. of acetone. The acetone solution is stirred with 120 ml. of ethanolic sodium hydroxide solution (1 N), and the mixture is refluxed for 1% hours.

At this point, a sample of the reaction mixture is separated therefrom and the product is isolated and recrystallized from isopropanol. It is identified as ethyl-8- trifiuoromethylphenothiazine 1 carboxylate, M.P. 95 96 C.

Example 4.Preparation of 8-trifluoromethylphenothiazine-l-carboxylic acid of the structural Formula I.

The remaining reaction mixture from Example 3 is concentrated under reduced pressure and the residue stirred with ether. The ethereal suspension is filtered and the solid is washed with additional ether. The combined ethereal solution is concentrated in vacuo to a semi-solid residue. The residue is dissolved in 75 ml. of warm ethanol, 15 ml. of aqueous sodium hydroxide (40% cone.) is stirred into the alcoholic solution, after which the mixture is heated at steam bath temperature for onehalf hour. The brown mixture is diluted with 200 ml. of distilled water. The resulting solution is treated with decolorizing charcoal, is filtered and the cooled filtrate is acidified with acetic acid. A bright yellow crystalline solid is collected, 8-trifluoromethylphenothiazine-l-carboxylic acid, and is washed with water and dried to give a product having a M.P. 238.5240 C. ((1).

Example 5.Preparation of 7 trifluoromethylphenothiazine-l-carboxylic acid of the structural Formula VIIIa A mixture of 14.0 g. (0.07 mole) of 2-amino-5-trifluoromethylthiophenol, 17.4 g. (0.07 mole) of 2-bromo- 3-nitrobenzoic acid, 38.7 g. (0.28 mole) of anhydrous potassium carbonate and 6 g. (0.03 mol) of sodium hydrosulfite (2-H O) is 125 ml. of dimethylformamide is stirred and heated for two hours at 125 to 130 C. Afterwards the cooled mixture is stirred into 1000 ml. of dilute acetic acid (12%). The solid that separated is washed with water, dried and recrystallized from 1:1 acetictrifiuoroacetic acid mixture. A yellow-orange solid is obtained, M.P. 244246 C.

Example 6.Preparation of 7,9-dichlorophenothiazine-1- carboxylic acid of the structural Formula VIIIa A mixture of 4.5 g. of the zinc salt of 2-amino-3,5- dichlorophenylmercaptan, 4 equivalents of sodium hydroxide and 2.5 g. of 2-bromo-3-nitrobenzoic acid are refluxed together in dimethylformamide. The cooled mixture is poured into ice water from which 7,9-dichlorophenothiazine-l-carboxylic acid is obtained on acidification with acetic acid, M.P. 282-283 C. (d).

Example 7.Preparation of 9 trifiuoromethylphenothiazine-l-carboxylic acid of the structural Formula VIIIa In like manner to Example 6, the zinc salt of Z-amino- 3-trifiuoromethylphenylmercaptan is reacted with 2- bromo-3-nitrobenzoic acid to yield 9-trifiuoromethylphenothiazine-l-carboxylic acid.

Example 8.Preparation of 2-trifluoromethylphenothiazine-l-carboxylic acid S-oxide of the structural Formula IX To a cooled solution (10 C.) of 3.11 g. of 2-trifiuoromethylphenothiazine-l-carboxylic acid (prepared as in Example 1) in 50 ml. of chloroform is added a solution of 2.2 g. of m-chloroperbenzoic acid (85% conc.) also in .40 ml. of chloroform, rapidly and drop-wise. The heat of reaction raises the mixture temperature to a maximum of 13 C. Afterwards the mixture is stirred in the cold for one hour then stirred at room temperature for three hours. The solid that forms is separated by filtration and is washed rapidly with ether. There is obtained 2.8 g.

(85 yield) of 2-trifiuoromethylphenothiazine-l-carboxylic acid S-oxide, M.P. l88189 C.

Example 9.-P'reparation of 8-trifluoromethylphenothiazine-l-carboxylic acid S-dioxide. of the structural Formula X A solution of 3.11 g. of 8-trifiuoromethylphenothiazinel-car'boxylic acid (prepared as in Examples 2 or 4) in ml. of glacial acetic acid is stirred as 15 ml. of hydrogen peroxide (30% come.) is added thereto. The resultant mixture is heated at reflux temperature for six hours, then is cooled and poured onto crushed ice. The solid which separates, 8-trifluoromethylphenothiazine-l-carboxylic acid S-dioxide, is removed and recrystallized from isopropanol, M.P. 328-329" C. (d).

Example l0.-Preparation of the intermediate methyl 2-[2-amino 4' trifluoromethylphenylmercapto]-3- nitrobenzoate of the structural Formula V Step I.A mixture of 10 g. of sodium hydroxide (in 10 ml. of water), 22.6 g. of the zinc salt of 3-amino-4- n.ercaptobenzotrifluoride and 22.6- g. of 2-bromo-3-nitrobenzoic acid in ml. of dimethylformamide is heated at steam bath temperature for three hours. The mixture is then concentrated under reduced pressure and the residue stirred with water. The mixture is filtered to remove insoluble salts and the filtrate is adjusted to pH 4. A gummy solid is removed and the filtrate now is adjusted to pH 2. The yellow solid is separated and recrystallized from toluene to give 2-[2-amino-4'-trifluoromethylphenylmercapto]-3-nitrobenzoic acid, M.P. 154155 C.

Step II.-A solution of 14 g. of 2-[2'-amino-4-trifiuoromethylphenylmercapto]-3-nitrobenzoic acid in 300 ml. of methanol is cooled and saturated with gaseous hydrogen chloride. The mixture is allowed to stand at room temperature for sixty hours after which the solvent is removed and the residue is recrystallized from methylcyclohexane to give methyl 2-[2'-amino-4'-trifluoromethylphenylmercapto]-3-nitrobenzoate, M.P. l02l03 C., the starting material of Example 3.

Example ll.Preparation of diethylaminoethyl 8-trifluoromethylphenothiazine-l-carboxylate hydrochloride of the structural Formula I 12.Preparation of 8-chloro-7-isopropoxythe structural Example phenothiazine-l-carboxylic acid of Formula VIIIa A stirred mixture of the zinc salt of 2-amino-4-chloro- S-isopropoxythiophenol (2.5 g., 0.005 mole), 2-bromo- 3-nitrobenzoic acid (2.46 g., 0.01 mole), granular anhydrous potassium carbonate (6.9 g., 0.05 mole) and N,N- dimethylformamide (20 ml.) is heated under nitrogen to during 0.75 hr. and at 120l32 C. for 1.5 hour.

The dark brown reaction mixture is cooled to room temperature and is filtered. The filtrate is diluted with water (350 ml.) and glacial acetic acid (10 ml.) is added. The resultant green emulsion is extracted exhaustively with ether. Most of the solvent is removed on a hot water bath, and the mixture is then brought to dryness under reduced pressure.

A dark semi-solid residue is extracted with a mixture (1:1) of ether-petroleum ether (20-40). After four decantations from a precipitating gum, the yellow solution is brought to dryness. Trituration of the residue with petroleum ether (20-40) provides a bright yelloworange solid (0.5 g., 15%), M.P. 226-226.5 C. (d). After two recrystallizations from benzene, an analytical 9 sample is obtained as bright yellow platelets, M.P'. 228- 230 C. (d).

Example 13.Preparation of S-methylmercaptophenothiazine-l-carboxylic acid of the structural Formula VIIIa In a manner similar to Example 12, reacting together the zinc salt of 2-amino-4-methylmercaptothiophenol and 2-bromo-3-nitrobenzoic acid gives S-methylmercaptophenothiazine-l-carboxylic acid.

Example 14.Preparation of \8-Methylsulfonylphenothiazine-l-carboxylic acid of the structural Formula VIIIa In a like manner to Example 12, the reaction of the zinc salt of 2-amino-4-methylsulfonylthiophenol and 2-bromo- 3-nitrobenzoic acid gives 8-methylsulfonylphenothiazinel-carboxylic acid.

Example 15.Preparation of 8-chlorophenothiazine-1- carboxylic acid of the structural Formula VIIIa A stirred mixture of 20 g. (0.1 mole) of 2amin0-4 chlorothiophenol hydrochloride, 25 g. (0.1 mole) of 2- bromo-3-nitrobenzoic acid and 60 g. (0.45 mole) of potassium carbonate in 200 ml. of dimethylformamide is refluxed for six hours. The reaction mixture is poured into several volumes of ice and water, is filtered and the filtrate is acidified with glacial acetic acid. Solid is removed, and is recrystallized from toluene to give a yellow crystalline compound, M.P. 280-282 C. (d).

Example 16.Preparation of 8-chloro-7-methylphenothiazine-l-carboxylic acid of the structural Formula VIIIa A stirred mixture of 7.0 g. (0.017 mole) of the zinc salt of 2-amino-4-chloro-5-methylthiophenol, 7.2 g. (0.03 mole) of 2-bromo-3-nitrobenzoic acid and 23 g. (0.18 mole) of potassium carbonate in 100 ml. of dimethylformamide is refluxed for seven hours. The cooled mixture is poured into several volumes of cold dilute acetic acid. The solid that separates is recrystallized from toluene to give a yellow crystalline compound, M.P. 272 C. (d).

Example 17.-Preparation of l-carbamyl-8-trifluoromethylphenothiazine of the structural Formula I Example 18.Preparation of 8-trifluoromethyl-1-[N-(diethylaminoethyl)carbamyl] phenothiazine hydrochloride of the structural Formula I A mixture of 5 g. (0.015 mole) of 8-trifluoromethylphenothiazine-l-carboxylic acid chloride (see Ex. 17) and 5 g. (0.035 mole) of diethylaminoethylamine in 200 ml. of ethyl ether are heated on the steam bath for fifteen minutes. The solution is cooled and washed successively with water, dilute sodium hydroxide and water. The resulting ethereal solution is dried and is treated with dry ethereal hydrogen chloride gas. The solid that separates is recrystallized from isopropanol, M.P. 178 to 180 C.

Example 19.Preparation of 8-fluorophenothiazine-l-carboxylic acid of the structural Formula VIIIa A stirred mixture of the zinc salt of 2-amino-4-fluorobenzenethiol (0.01 mole), 2-bromo-3-nitrobenzoic acid (0.002 mole), granular anhydrous potassium carbonate (0.1 mole) in N,N-dimethylformamide (75 ml.) is heated under nitrogen to 120 C. during /1 of an hour and then at 120140 C. for 1 /2 to 2 hours. The reaction mixture is cooled to room temperature and it is then filtered. Dilution of the filtrate with water produces a precipitate. The latter is collected, is washed with water, and is dried. Recrystallization from xylene gives yellow needles of 8- fluorophenothiazine-l-carboxylic acid, M.P. 250-252 C.

Example 20.Preparation of 8-trifluoromethylsulfonylphenothiazine 1 carboxylic acid of the structural Formula VIIIa In a manner similar to Example 19, reacting together the zinc salt of 2-amino-4-trifluoromethylsulfonylbenzenethiol and 2-bromo-3-nitrobenzoic acid upon recrystallization from ethanol-water gives yellow needles of S-trifluoromethylsulfonylphenothiazine 1 carboxylic acid, M.P. 277.5-280 C. (d).

Example 21.Preparation of 7-methoxyphenothiazine-1- carboxylic acid of the structural Formula VIIIa In a manner similar to Example 19, reacting together the zinc salt of 2-amino-5-methoxybenzenethiol and 2- bromo-3-nitrobenzoic acid upon recrystallization from toluene gives orange plates of 7-methoxyphenothiazine-1- carboxylic acid, M.P. 232234 C. (d).

Example 22.Preparation of 7-trifluoromethoxyphenothiazine-l-carboxylic acid of the structural Formula VIIIa In a manner similar to Example 19, reacting together the zinc salt of 2-amino-5-trifluoromethoxybenzenethiol and 2-bromo-3-nitrobenzoic acid upon recrystallization from toluene gives yellow needles of 7-trifluoromethoxyphenothiazine-l-carboxylic acid, M.P. 208.5-211.5 C.

Example 23.Preparation of 7,8 dimethoxyphenothiazine-1-carboxylic acid of the structural Formula VIIIa In a manner similar to Example 19, reacting together the zinc salt of 2-amino-4,S-dimethoxybenzenethiol and 2-bromo-3-nitrobenzoic acid upon recrystallization from toluene gives orange needles of 7,8-dimethoxyphenothiazined-carboxylic acid, M.P. 230-234 C. ((1).

Example 24.Preparation of 7,S-dimethylphenothiazinel-carboxylic acid of the structural Formula VIIIa In manner similar to Example 19, reacting together the zinc salt of 2-amino-4,S-dimethylbenzenethiol and 2 bromo-3-nitrobenzoic acid upon recrystallization from xylene gives yellow-orange needles of 7,8-dimethylphenothiazine-l-carboxylic acid, M.P. 261263 C. (d).

Example 25 .Preparation of 8-phenylphenothiazine-1- carboxylic acid of the structural Formula VIIIa.

In a manner similar to Example 19, reacting together the zinc salt of 2-amino-4-phenylbenzenethiol and 2- bromo-3-nitrobenzoic acid upon recrystallization from toluene gives yellow needles of S-phenylphenothiazine-lcarboxylic acid, M.P. 279281 C. (d).

Example 26.Preparation of S-trifluoromethylphenothiazine-l-carboxylic hydrazide of the structural Formula I A mixture of 11 g. (0.3 mole) of hydrazine (25% aqueous) and 10 g. (.03 mole) of ethyl S-trifluoromethylphenothiazine-l-carboxylate in ml. of methanol is stirred and heated under reflux for 3 hours. The solvent is removed in vacuo, and the residue extracted between ether and dilute sodium hydroxide. The ether layer is concentrated and the resulting solid recrystallized twice from toluene to yield 7.5 g. of the yellow crystalline solid product, M.P. 184-185 C.

Example 27.Preparation of 1- -hydroxymethyl-8-trifluoromethylphenothiazine of the structural Formula I A solution of 25 g. (0.081 mole) of 8-trifluoromethylphenothiazine-l-carboxylic acid (Ex. 2) in 500 ml. of dry ether is added over a thirty minute period to a stirred suspension of 10.7 g. (0.282 mole) of lithium aluminum hydride in 250 ml. of dry ether. The reaction mixture is cooled in ice, and is maintained under a nitrogen atmos phere during the addition. Afterwards, it is allowed to warm to room temperature and is stirred an additional two hours. It is again cooled during the cautious addition of 10 ml. of distilled water, followed by 100 ml. of sulfuric acid N). The ether layer is separated and washed successively with water, dilute sodium hydroxide and water, and is then evaporated to dryness to give 23.6 g. of crude alcohol, M.P. 9598 C. Recrystallization of 5 g. of crude product from 47.5 ml. methanol/ 35 ml. distilled water gives 4.1 g. of pure l-hydroxymethyl-S-trifluoromethylphenothiazine, M.P. 100101 C.

Example 28.Preparation of ethyl-N-ethyl-S-trifiuoromethylphenothiazine-l-carboxylate and N-ethyl-8-trifluoromethylphenothiazine-l-carboxylic acid of the structural Formula I A solution of g. (0.03 mole) of ethyl-S-trifluoromethylphenothiazine-l-carboxylate (Ex. 3) in 25 ml. dimethylformamide and 25 ml. benzene is treated with 2 g. of sodium hydride (55%) and the reaction stirred onehalf hour. Twenty-eight g. (0.1 mole) of ethyl iodide is then added and the reaction refluxed for 3 hours. The benzene is removed in vacuo and the residue extracted between water and ether. The ether layer is concentrated to an oil, which is chromatographed on silica gel and eluted with 10% benzenecyclohexane. Eluates from the first band off the column are concentrated and cooled to produce a white solid which is recrystallized from ethanol to yield ethyl-N-ethyl-8-trifluoromethylphenothiazine-1- carboxylate, M.P. 4850 C. Alkaline hydrolysis of the ester gives the corresponding acid, N-ethyl-8-trifluoromethylphenothiazine-l-carboxylic acid, M.P. 146-170 C.

Example 29.-Preparation of 8-trifluoromethylphenothiazine-l-hydroxamic acid of the structural Formula I A mixture of 10 g. (.03 mole) of 8-trifiuoromethylphenothiazine-l-carboxylic acid chloride (see Ex. 18) 8 g. (0.12 mole) of hydroxylamine hydrochloride, and 13 g. (0.12 mole) of anhydrous sodium carbonate is stirred together in 200 ml. of ether as one ml. of water is added dropwise. A mildly exothermic reaction will take place with a red to yellow color change. The reaction is further stirred one-half hour, then filtered, and the filtrate concentrated to dryness. The residue is purified by column chromatography to yield 6.5 g. (65%) of yellow solid product, M.P. 165-166 C.

Example 30.Preparation of 9-methylphenothiazine-1- carboxylic acid of the structural Formula IVb Three hundred milliliters (0.47 mole) of 15% butyl lithium solution in hexane is added to g. (0.094 mole) of l-methylphenathiazine [Massie, SP. and Kadaba, P.K., J. Org. Chem. 21, 347 (1956)], in 600 ml. of dry ether at ice bath temperature. The reaction mixture is refluxed for 3.5 hours, poured over Dry Ice, and acidified with dilute hydrochloric acid. The organic layer is separated and extracted with dilute sodium hydroxide solution. The basic extracts are acidified step-wise, first with glacial acetic acid to a pH of 5.5 to yield 9 g. of solid, M.P. 141- 142 C. (d) [I]; then, with hydrochloric acid to yield 6.2 g. of solid, M.P. 135138 C. ((1) [II]. Purification of fraction [I] by chromatography on acid alumina gives primarily 9-methylphenothiazine-l-carboxylic acid, M.P. 235.5-237" C. (d). A similar treatment of fraction [II] gives mainly phenothiazine-l-acetic acid, M.P. 154-155 C. (d).

Example 31.-Preparation of 2-trifiuoromethyl-9-methylphenothiazine-l-carboxylic acid of the structural Formula IVb To an ice-cooled suspension of 12.4 g. (0.32 mole) of lithium auminum hydride in 300 ml. of dry ether is added a filtered solution of 42.8 g. (0.32 mole) of aluminum chloride in 150 ml. of ether, followed by a solution of 20 g. (0.064 mole) of 8-trifluoromethylphenothiazine-1- carboxylic acid in 500 ml. of ether. After refluxing for five hours, the reaction mixture is decomposed with dilute sulfuric acid solution. The ether layer is separated to yield 19.2 g. of a dark green oil which is purified by chromatography and sublimation to yield l-methyl-S-trifluoromethylphenothiazine, M.P. 9798.5 C.

One hundred milliliters of 15% butyl lithium solution in hexane is added at ice bath temperature to a solution of 6.6 g. (0.0235 mole) of 1-methyl-8-trifluoromethylphenothiazine in 300 ml. of dry ether. The cooled mixture is stirred for 3.5 hours, poured over dry ice, and acidified with dilute hydrochloric acid. The organic layer is separated and extracted with dilute sodium hydroxide solution. The basic extracts are acidified with concentrated hydrochloric acid, and the solid that separates is recrystallized from xylene to give 2-trifiuoromethyl-9-methylphenothiazine-l-carboxylic acid, M.P. 223224 C. ((1).

Example 32.Preparation of Z-hydroxyphenothiazine-lcarboxylic acid of the structural Formula I An intimate mixture of 0.66 g. (0.002 mole) of 2-methoxyphenothiazine-l-carboxylic acid (Ex. 36) and 1.4 'g. (0.012 mole) of pyridine hydrochloride is heated for 23 minutes at an oil bath temperature of -153 C. The cooled melt is stirred in water, extracted with ether, and the extracts lastly extracted with dilute sodium hydroxide. The basic extracts, after acidification with concentrated hydrochloric acid, yield 0.29 g. of 2-hydroxyphenothiazine-l-carboxylic acid, M.P. 200-203 C. ((1).

Example 33.-Preparation of 8-trifluoromethylphenothiazine-l-acetic acid of the structural Formula I A mixture of 10 ml. of phosphorus trichloride and 10 ml. of chloroform is stirred at room temperature as 5.9 g. (0.02 mole) of 1-hydroxymethyl8-trifluoromethylphenothiazine followed by 1 ml. of dimethylformamide is added thereto. Stirring is followed for four hours at which time the entire reaction is concentrated under reduced pressure to a thick oil. The oil is redissolved in ether and chromatographed on neutral alumina with hexane as the eluent. 1- chloromethyl-8-trifluoromethylphenothiazine is recovered as the most rapid moving eluted fraction.

A methanolic solution (40 ml.) of 3.2 g. (0.01 mole) of 1-chloromethyl-8-trifluoromethylphenothiazine and 1.0 g. (0.015 mole) if potassium cyanide is refluxed for 8 hours. The total mixture is concentrated under reduced pressure to a semi-solid which is than washed well with water. Residual crude 8-trifluoromethylphenothiazine-1 acetonitrile is purified by chromatography on neutral alumina.

A solution of 3.1 g. (0.01 mole) of S-trifluiromethylphenothiazine-l-acetonitrile in 25 ml. of ethanolic potassium hydroxide (5%), containing 5 ml. of water, is heated under reflux for thirty hours. The resulting solution is poured into five volumes of distilled water and is acidified with concentrated hydrochloric acid to precipitate the ace tic acid. Purification of 8-trifluoromethylphenothiazine-1- acetic acid is accomplished by resolution in dilute alkali, decolorization of the solution with activated charcoal and precipitation with hydrochloric acid.

Example 34.-Preparation of 8-trifluoromethylphenothiaz1ne-l-thiocarboxylic acid of the structural Formula I A solution of potassium hydrosulfide, prepared from 1.4 g. (0.025 mole) of potassium hydroxide and hydrogen sulfide in 20 ml. of methanol, is cooled as 3.3 g. (0.01 mole) of S-trifluoromethylphenothiazinyl-l-carboxylic acid chloride (see Ex. 17) is added portionwise thereto. After the addition is completed, the mixture is allowed to set overnight. The mixture is concentrated under reduced pressure, the residue is redissolved in distilled water, and the filtered solution is treated with concentrated hydrochloric acid to precipitate the thio acid. The orange solid is purified by recrystallization fromtoluene.

A mixture of 5.8 g. (0.025 mole) of 2-amino-4-trifiuoromethylbenzenethiol hydrochloride, 5.0 'g. (0.025 mole) of 2-nitro-3-chlorobenzoic acid and 14 g. (0.1 mole) of anhydrous potassium carbonate in 150 ml. of dry dimethylformamide is stirred and heated at reflux for twenty-four hours. At this point 8 g. of additional potassium carbonate is added and refluxing continued another twenty-four hours. The cooled mixture is filtered and the filtrate concentrated to dryness under reduced pressure. A dark residue is extracted with aqueous sodium hydroxide (1%) and the combined extracts acidified with hydrochloric acid. The amorphous separation is removed by ether extraction and the combined ether extract is chromatographed on acid alumina using aqueous-isopropyl alcohol as the eluant. Recrystallization of the yellow fraction from benzene gives 8trifiouromethylphenothiazine-4-carboxylic acid, M.P. 220223 C. ((1).

Example 36.Preparation of 2-methoxyphenothiazine-1- carboxylic acid of structural Formula I In a manner similar to Example 1, 10 g. (0.044 mole) of Z-methoxyphenothiazine [Cymerman-Craig, 1., Rogers, W. P. and Tate, M. E., Austral. J. Chem., 9, 397 (1956)] is reacted with 200 mls. of hexane solution of butyl lithium (10.5 .g. per 100 ml.) to give 2-methoxyphenothiazine-1- carboxylic acid, M.P. 161-162 C.

I claim:

1. A chemical compound having the structural formula:

X II

.0! Q X Y H wherein:

Y is COR, CH OH, or -CH COOH, with said Y being limited to the one or four position;

R represents hydroxy, alkoxy, mercapto, dialkylaminoalkoxy, NRR, -NHNH or NHOH, the alkyl moieties each having one to three carbon atoms;

R and R" are both hydrogen, or one is dialkylaminoalkyl, the alkyl moieties each having one to three carbon atoms;

RIIIRIPINSOF AlkCO, lower alkyl straight or branched to five carbon atoms, lower alkoxy straight or branched to five carbon atoms, phenyl ,or CH OH;

X" is at least one of H, OH, CH CF halogen, CH S, CF O, CF S-, CH SO, CF SO, CH SO CF SO R"RNSO AlkCO, or lower alkyl to five carbon atoms; but X, X and X are never all hydrogen or all a moiety other than hydrogen at the same time and X" is not halogen when either X or X is halogen;

R and R are hydrogen or alkyl having one to three carbon atoms;

Alk is alkyl having one to three carbon atoms; and

Z is sulfur.

2. A chemical compound having the structural formula:

14 wherein:

R represents hydroxy, alkoxy, mercapto, dialkylaminoalkoxy, NRR, NHNH or NHOH, the alkyl moieties each having one to three carbon atoms;

R and R are both hydrogen, or one is dialkylaminoalkyl, the alkyl moieties each having one to three carbon atoms;

X and X are at least one of H, OH, CF halogen, NH CF 0, CH S, CF S, CH SO, CF SO, CH SO CF SO R'RNSO AlkCO--, lower alkyl straight or branched to five carbon atoms, phenyl, or -CH OH, with one of X and X being limited to the 8-position;

X" is at least one of H, CP halogen, CH S CF S, CH SO, CF SO, CH SO CF SO R"RNSO AlkCO, or lower alkyl straight or branched to five carbon atoms, but X, X and X are never all hydrogen or a moiety other than hydrogen at the same time and X is not halogen when either X or X is halogen;

R and R are hydrogen or all alkyl having one to three carbon atoms; and

Alk is alkyl having one to three carbon atoms.

3. A chemical compound in accordance with claim 2 in which R is hydroxy.

4. A chemical compound in accordance with claim 3 in which X is CE, and X and X are hydrogen.

5. A chemical compound in accordance with claim 4 in which X is 8-CF being the compound 8-trifluoromethylphenothiazine-l-carboxylic acid.

6. A chemical compound in accordance with claim 4 in which X is 9-CF being the compound 9-trifiuoromethylphenothiazine-l-carboxylic acid.

7. A chemical compound in accordance with claim 3 in which X and X are hydrogen and X is 2-CF being the compound 2-trifluoromethylphenothiazine-l-carboxylic acid.

8. A chemical compound in accordance with claim 3, in which X and X are hydrogen and X is 8-CF SO being the compound -8-trifiuoromethylsulfonylphenothiazine-l-carboxylic acid.

9. A chemical compound in accordance with claim 3 in which X is hydrogen and X and X are 7,8-dimethyl, being the compound 7,8dimethylphenothiazine-l-carboxylic acid.

10. A chemical compound in accordance with claim 2 in which X and X are hydrogen, R is ethoxy and X is 8-CF being the compound ethyl-S-trifluoromethyL phenothiazine-l-carboxylate.

11. A chemical compound in accordance with claim 1, wherein X is 8-CF X and X" are hydrogen, Y is.l- CH OH, and Z is sulfur, being the compound l-hydroxymethyl-8trifluoromethylphenothiazine.

12. A process for preparing a mono-, di-, or tri-substituted phenothiazine carboxylic acid, having the following basic structure:

s E21 lol Y X H wherein X, X and X represent at least one of H, CF halogen, NO NH CH S, CF S-, CH SO, CF SO, CH SO CF SO lower alkyl to 5 carbon atoms, or lower alkoxy to 5 carbon atoms and X is not halogen when either X or X is halogen.

by treating a substituted Z-aminothiophenol having the structural formula:

NHz

in which X or X are as defined above; with a substan tially equimolecular amount of an appropriately substituted 2-halo-3-nitrobenzoic acid in the form of its potassium, sodium or zinc salt having the structural formula:

COOH

XII

Hal

in which X" is as defined above, and Hal is halogen; in a polar dimethylformamide solvent with at least three equivalents of a strong base selected from the group consisting of alkali metal hydroxide and carbonate, refluxing above 100 C., and introducing the reaction mixture into acid medium to precipitate the product.

13. The method in accordance with claim 12 characterized in that the polar solvent is N,N-dimethylformamide, the base is anhydrous potassium carbonate, and the reaction temperature is maintained above 100 C.

14. The method in accordance with claim 12 in that the polar solvent is N,N-dimethylformamide, the 2-aminophenol is 3-amino-4-mercaptobenzotrifiuoride, the nitrobenzoic acid is 2-bromo-3-nitrobenzoic acid, the base is anhydrous potassium carbonate, the reaction temperature is maintained above 100 C., and the product is 8- trifiuoromethylphenothiazine-l-carboxylic acid.

References Cited UNITED STATES PATENTS 3,341,534 9/1967 Driscoll 260243 3,334,092 8/ 1967 Driscoll 260243 3,074,939 1/1963 Davis 260-243 OTHER REFERENCES Driscoll et al.: J. Heterocyclic Chem., vol. 2, pp. 272- 75, September 1965.

Cauquil et al.: Comp. Rend., vol. 240, pp. 1997-2000 (1955).

Cauquill et al.: Soc. Chim. de France Bull., Ser. 5, pp. 590-97 (March 1964).

Cauquil et al.: Soc. Chim de France Bull., pp. 768- 782 1955).

Cauquil et al.: Soc. Chim. de France Bull., pp. 1061- 75 (1955).

Sen et al.: J. Indian Chem. Soc., pp. 202-04, vol. (1958).

Galbreath et al.: J. Org. Chem., vol. 23, pp. 1804-6 (1958).

Derwent: Fine Chem. Pat. 1., vol. 3, No. 40, G. 3, p. 7 (Oct. 8, 1963).

Antoni: Soc. Chim de France, pp. 2214-16 (September 1964).

Baltzly et al.: J. Am. Chem. Soc., vol. 68, pp. 2673- 78 (1946).

HENRY R. JILES, Primary Examiner H. I. MOATZ, Assistant Examiner US. Cl. X.R., 

